GBT1118, a potent allosteric modifier of hemoglobin O2affinity, increases tolerance to severe hypoxia in mice

Abstract

Adaptation to hypoxia requires compensatory mechanisms that affect O2transport and utilization. Decreased hemoglobin (Hb) O2affinity is considered part of the physiological adaptive process to chronic hypoxia. However, this study explores the hypothesis that increased Hb O2affinity can complement acute physiological responses to hypoxia by increasing O2uptake and delivery compared with normal Hb O2affinity during acute severe hypoxia. To test this hypothesis, Hb O2affinity in mice was increased by oral administration of 2-hydroxy-6-{[(2 S)-1-(pyridine-3-carbonyl)piperidin-2yl] methoxy}benzaldehyde (GBT1118; 70 or 140 mg/kg). Systemic and microcirculatory hemodynamics and oxygenation parameters were studied during hypoxia in awake-instrumented mice. GBT1118 increased Hb O2affinity and decreased the Po2at which 50% of Hb is saturated with O2(P50) from 43 ± 1.1 to 18.3 ± 0.9 mmHg (70 mg/kg) and 7.7 ± 0.2 mmHg (140 mg/kg). In a dose-dependent fashion, GBT1118 increased arterial O2saturation by 16% (70 mg/kg) and 40% (140 mg/kg) relative to the control group during 5% O2hypoxia. In addition, a GBT1118-induced increase in Hb O2affinity reduced hypoxia-induced hypotension compared with the control group. Moreover, microvascular blood flow was higher during hypoxia in GBT1118-treated groups than the control group. The increased O2saturation and improved blood flow in GBT1118-treated groups preserved higher interstitial tissue Po2than in the control group during 5% O2hypoxia. In conclusion, increased Hb O2affinity enhanced physiological tolerance to hypoxia, as evidenced by improved hemodynamics and tissue oxygenation. Therefore, pharmacologically induced increases in Hb O2affinity become a potential therapeutic approach to improve tissue oxygenation in pulmonary diseases characterized by severe hypoxemia.NEW & NOTEWORTHY This study establishes that pharmacological modification of hemoglobin O2affinity can be a promising and novel therapeutic strategy for the treatment of hypoxic hypoxia and paves the way for the clinical development of molecules that prevent hypoxemia.